"The study is exciting because it really changes how we think about what is happening in treated patients," says Angela McLean. "It helps explain why some strategies that tried to clear the reservoir have failed." (Credit: iStockphoto)

HIV is still replicating in lymphoid tissue, even when it is undetectable in the blood of patients on antiretroviral drugs, new research shows.

The findings provide a critical new perspective on how HIV persists in the body despite potent antiretroviral therapy.

“We now have a path to a cure.”

“We now have a path to a cure,” says Steven Wolinsky, chief of infectious diseases at Northwestern University’s Feinberg School of Medicine. “The challenge is to deliver drugs at clinically effective concentrations to where the virus continues to replicate within the patient.”

Combinations of potent antiretroviral drugs quickly suppress HIV to undetectable levels in the bloodstream of most patients, but HIV persists in a viral reservoir. If patients stop their drugs, the virus rapidly rebounds in the blood.

For several reasons, up until now most scientists believed the reservoir only contained long-lived infected cells in a resting state rather than newly infected cells. First, no one had seen viruses with the new genetic mutations that inevitably arise when HIV completes cycles of growth. Second, most patients don’t develop the drug resistance mutations, which might seem likely, if HIV was growing in the presence of drugs.

Drug sanctuaries

For the new study, published in the journal Nature, researchers examined viral sequences in serial samples of cells from lymph nodes and blood from three HIV-infected patients at the University of Minnesota who had no detectable virus in their blood. They found the viral reservoir was, in fact, constantly replenished by low-level virus replication in lymphoid tissue with infected cells then moving from these protected sanctuaries into the blood.

Because infected cells in drug-sanctuaries within lymphoid tissue can still produce new viruses, infect new target cells, and replenish the viral reservoir, it has not been possible to purge the body of latently infected cells and eradicate the virus.

A mathematical model tracked the amount of virus and the number of infected cells as they grew and evolved in drug sanctuaries, and then moved through the body. The model explains how HIV can grow in drug sanctuaries in lymphoid tissue where antiretroviral drug concentrations are lower than in the blood, and why viruses with mutations that create high-level drug-resistance do not necessarily emerge.

The findings provide a new perspective on how HIV persists in the body despite potent antiretroviral therapy. The study also explains why the development of drug resistance is not inevitable when virus growth occurs in a place where drug concentrations are very low.

Most importantly, the work highlights how important it is to deliver high concentrations of antiretroviral drugs to all locations in the body where HIV can grow. Drugs that penetrate the newly discovered sanctuaries will be a prerequisite to the elimination of the viral reservoir and, ultimately, a step towards a cure.

“The study is exciting because it really changes how we think about what is happening in treated patients,” says coauthor Angela McLean, professor of mathematical biology at Oxford University. “It helps explain why some strategies that tried to clear the reservoir have failed.”

Other researchers from Northwestern, Oxford, University of Minnesota, the Fred Hutchinson Cancer Research Center in Seattle, Temple University, the Korean National Institutes of Health, the University of Nebraska Medical Center, King’s College London, the University of Edinburgh, and Centro de Investigação em Biodiversidade e Recursos Genéticos Universidade do Porto in Portugal are coauthors of the study.

The National Institutes of Health, the Medical Research Council, the Framework Programme for Research and Technological Development, the European Research Council, the Oxford Martin School, All Souls College and the Royal Society supported the work.